Heme oxygenase is an enzyme which was first implicated in the degradation of molecules of heme into biliverdin. Abraham et al., Int. J. Biochem 20(6): 543-558 (1988), the disclosure of which is incorporated by reference herein. The enzyme was recognized to be inducible by heavy metals, such as Cr, Mn, Fe, Ni, Cu, Zn, Au, Hg, Pb, Cd, Sn, Pt, and Sb. However, cobalt is regarded as the most powerful inducer of the enzyme, and has been seen to induce a 45 fold increase in the enzyme. The enzyme is also induced by heme derivatives and by vitamin B12. Abraham, supra. The enzyme was recognized in human corneal epithelium, as per Abraham et al., Inv. Ophthal & Vis. Sci. 28(9): 1464-1472 (1987). This paper suggests that the enzyme is implicated in drug detoxification in the corneal epithelium, a phenomenon that had been observed prior to this paper. Abraham et al. also note that levels of the enzyme cytochrome P-450 monooxygenase are dependent upon heme oxygenase levels and that the P-450 monooxygenase enzyme is implicated in the metabolism of arachidonic acid. Two metabolites are noted in particular and, while not identified, one metabolite is characterized as an Na.sup.+ -K.sup.+ ATPase inhibitor, and the other as a vasodilator. Masferrer et al. in Inv. Opthal & Vis. Sci. 31(3): 535-539 (March, 1990), identify the Na.sup.+ -K.sup.+ ATPase inhibitor as 12(R)-hydroxy-eicosatetraenoic acid, and this will be described as "12(R)-HETE" hereafter. Masferrer et al. show that upon administration of 12(R)HETE to rabbits having normal intraocular pressure (IOP), the pressure dropped, dramatically. IOP, as will be recognized to the skilled artisan, is a condition characterized by a relationship between aqueous humor production and drainage. Thus, Masferrer et al. taught that some ocular disorders could be treated via the administration of 12(R)HETE.
Masferrer et al., in an earlier paper, i.e., Inv. Ophthal. & Vis. Sci 30(3); 454-459 (1989) identified the previously mentioned vasodilator as 12-hydroxy-5,8,14-eicosatrienoic acid (12(R)DIHETE). This paper suggested the administration of this compound, referred to as "12-DIHETE" hereafter, would provoke massive vasodilation of conjunctival blood vessels in the eye, breakdown of the blood aqueous barrier, chemotaxis of inflammatory leukocytes and invasion of the cornea by new blood vessels. Up to a 30-fold increase of aqueous humor protein was observed.
The previously described inducibility of heme oxygenase by heavy metals, certain metalloporphyrins and vitamin B12 is of relevance in connection with Sacerdoti et al., Science 234: 388-390 (1989). This paper noted an increase in the metabolites of arachidonic acid in the kidneys of spontaneously hypertensive rats. Treatment with stannous chloride, (SnCl.sub.2) was found to deplete the renal cytochrome P-450, and to return the blood pressure of the subject animals to a normal level.
In view of the art on 12(R)-HETE and heme oxygenase, it was therefore surprising that eye disorders characterized by ocular swelling could be treated by administering a compound which, ultimately, reduces the level of 12(R)-HETE in the eye. This is surprising because the art would seem to suggest that 12(R)-HETE could be added to the eye to reduce IOP. It was not taught or suggested, however, that manipulation of the heme oxygenase pathway could eventually decrease the amounts of 12(R)-HETE and 12(R)-DIHETE, with an observable physiological effect. It is this effect which is the subject of the invention, and which will be explained in greater detail in the description which follows.